A Comparison of Clinical Outcomes Among Undenatured Collagen Type II, Glucosamine Sulfate, and Diacerein on Osteoarthritic Knee Treatment: A Randomized Clinical Trial.

Background: Knee osteoarthritis (OA) causes significant disability with limited effective treatments. Undenatured collagen type II (UC-II), prescription-grade crystalline glucosamine sulfate (pCGS), and diacerein have been proposed as alternatives to conventional analgesics, but their comparative efficacy remains uncertain. We hypothesized that each supplement would demonstrate superior efficacy over placebo in reducing total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score at Week 24 in patients with mild-to-moderate knee OA. Methods: This 4-arm, randomized, double-blind, placebo-controlled trial enrolled 216 Thai adults with symptomatic knee OA (Kellgren-Lawrence grade 2-3). Participants received UC-II (40 mg once daily), pCGS (500 mg 3 times daily), diacerein (50 mg once to twice daily), or placebo for 24 weeks, with follow-up to 36 weeks. The primary outcome was total WOMAC score (22 items; pain, stiffness, and physical function; scored 0-220, higher = worse) at Week 24. Analyses followed intention-to-treat principles using multiple imputation by chained equations (m = 10) and linear mixed-effects models. Results: Of 216 randomized Thai participants, 208 (96.3%) completed follow-up (mean age 61.7 ± 7.1 years; 90.9% female; 73.6% Kellgren-Lawrence grade 2). At Week 24, no supplement demonstrated superiority over placebo. Between-group differences in total WOMAC score were as follows: UC-II -4.7 (95% CI -18.6 to 9.1), pCGS -8.1 (95% CI -21.8 to 5.7), and diacerein -12.3 (95% CI -25.9 to 1.3). All 95% CIs included zero, and all point estimates were at or below, and none clearly exceeded, the minimum clinically important difference threshold. At 36 weeks, results were consistent: UC-II -1.8 (95% CI -15.5 to 12.0), pCGS -4.8 (95% CI -18.4 to 8.7), and diacerein -1.3 (95% CI -14.9 to 12.3). Secondary outcomes including pain scores, joint space width, and functional performance showed no significant between-group differences. Adverse events were mild and comparable across groups; no serious adverse events occurred. Conclusions: Among Thai patients with mild-to-moderate knee OA, UC-II, pCGS, and diacerein did not demonstrate superiority over placebo in reducing pain or improving function at 24 weeks. These findings do not support their routine use as monotherapy for knee OA. Trial Registration: Thailand Clinical Trial Registry (TCTR20210901003). Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.